The preocular tear film plays a critical role in maintaining ocular surface integrity, protecting against microbial challenge and preserving visual acuity. Tear film dysfunction, in turn, may severely impact the eye and lead to desiccation of the corneal epithelium, ulceration and perforation of the cornea, an increased incidence of infectious disease, and pronounced visual impairment and blindness. Countless people suffer from tear film disorders, which are termed dry eye syndromes and are classified into 2 major types: aqueous-deficient and evaporative. Aqueous- deficient dry eye is due to decreased tear secretion from the lacrimal gland. An example is Sjogren s syndrome, a common autoimmune disease that afflicts primarily women and destroys the lacrimal gland. Evaporative dry eye is typically caused by meibomian gland dysfunction and may be a major cause of dry eye during menopause and aging. The long range objectives of this grant application are to test our hypotheses that: (1) androgens are extremely important in the physiological regulation of the lacrimal and meibomian glands, as well as the production of the tear film; and (2) gender, sex steroid hormones, and in particular androgen deficiency, are critical etiologic factors in the pathogenesis of both aqueous-deficient and evaporative dry eye syndromes. Experimental procedures involve mouse and rabbit models, differential display techniques, RT-PCR, cloning, Northern and Southern blots, in situ hybridization, cell cultures, immunoassays, HPLC/mass spectrometry, enzyme assays, histology, image analysis, hormone reconstitution experiments, as well as clinical studies with humans. Our specific aims are to: (1) define the mechanism(s) underlying the androgen-induced suppression of lacrimal gland inflammation in mouse models of Sjogren s syndrome; (2) identify the genes and proteins involved in the androgen control of the rabbit meibomian gland; (3) determine whether androgens regulate the lacrimal and meibomian glands of humans; (4) examine whether a correlation exists between total androgen deficiency and dry eye syndromes in women with Sjogren s syndrome; and (5) evaluate whether the human lacrimal and meibomian glands contain the enzymatic machinery necessary for the local synthesis and action of sex steroids. Results from the studies should significantly advance our understanding of the processes by which gender and sex steroids influence the anterior segment of the eye. In addition, findings may have health relatedness for the eye, because they: (1) explore the regulation of the tear film; and (2) may lead to the development of specific therapies for the clinical treatment of dry eye syndromes.